Activation of SIRT1 by Hyperbaric  Oxygenation Promotes Recovery of Motor Dysfunction in Spinal Cord Injury Rats

2020 ◽  
Author(s):  
Huiqiang Chen ◽  
Mengyu Yao ◽  
Zhibo Li ◽  
Ranran Xing ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Molecular Mechanisms ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Inflammatory Cascade ◽  
Locomotor Function ◽  
Cord Injury

Abstract Background: Emerging evidence demonstrated that hyperbaric oxygenation (HBO) therapy improved the locomotor dysfunction following spinal cord injury (SCI). Sirtuin1(SIRT1) has been characterized as neuroprotection in nerve system. However, whether SIRT1 is involved in alleviation of locomotor function by HBO therapy is unclear. Methods: The Basso, Beattie Bresnahan (BBB) locomotor rating scale was used to evaluate the open-field locomotor function. Western blot, real-time quantitative reverse transcription polymerase chain reaction, SIRT1 activity assay and enzyme-linked immunosorbent assays were performed to explore the molecular mechanisms in adult Sprague-Dawley rats. Results: We found that series HBO therapy significantly improved the locomotor dysfunction and ameliorated the decrease mRNA, protein and activity of spinal cord SIRT1 induced by traumatic SCI injury in rats. In addition, intraperitoneal injection SIRT1 antagonist EX-527 abolished the beneficial effects of series HBO treatment on locomotor deficits and SIRT1 activity loss caused by traumatic SCI injury. However, the rats undergone both series HBO therapy and SIRT1 agonist SRT1720 got the higher BBB score than that undergone series HBO treatment only. Importantly, series HBO treatment following the traumatic SCI injury inhibited the inflammatory cascade and apoptosis-related protein, which was retained by EX-527 and enhanced by SRT1720. Furthermore, EX-527 blocked the enhanced induction of autophagy series with HBO application. Conclusion: These findings demonstrated a new mechanism for series HBO therapy involving activation of SIRT1 and subsequent modulation of inflammatory cascade, apoptosis and autophagy, which contributed to the recovery of motor dysfunction. Key words: HBO, SIRT1, motor dysfunction, inflammation, autophagy, apoptosis

Combination Therapy With Hyperbaric Oxygen and Erythropoietin Inhibits Neuronal Apoptosis and Improves Recovery in Rats With Spinal Cord Injury

2019 ◽  
Vol 99 (12) ◽  
pp. 1679-1689 ◽  
Author(s):  
Yue Zhou ◽  
Peng Su ◽  
Zhenzhen Pan ◽  
Dong Liu ◽  
Yanping Niu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyperbaric Oxygen ◽  
Neuronal Apoptosis ◽  
Molecular Mechanisms ◽  
Rating Scale ◽  
B Cell Lymphoma ◽  
Locomotor Function ◽  
Therapeutic Benefits ◽  
Cord Injury

Abstract Background Apoptosis plays an important role in various diseases, including spinal cord injury (SCI). Hyperbaric oxygen (HBO) and erythropoietin (EPO) promote the recovery from SCI, but the relationship between apoptosis and the combination therapeutic effect is not completely clear. Objective The purpose of this study was to investigate the effects of HBO and EPO on SCI and the mechanisms that underlie their therapeutic benefits. Design The study was designed to explore the effects of HBO and EPO on SCI through a randomized controlled trial. Methods Sixty young developing female Sprague-Dawley rats were randomly divided into groups of 12 rats receiving sham, SCI, HBO, EPO, or HBO plus EPO. The SCI model was modified with the Allen method to better control consistency. HBO was performed for 1 hour per day for a total of 21 days, and EPO was given once per week for a total of 3 weeks. Both methods were performed 2 hours after SCI. Locomotor function was evaluated with the 21-point Basso-Beattie-Bresnahan Locomotor Rating Scale, an inclined-plane test, and a footprint analysis. All genes were detected by Western blotting and immunohistochemistry. The level of cell apoptosis was determined by Hoechst staining. Results The results showed that HBO and EPO promoted the recovery of locomotor function in the hind limbs of rats by inhibiting the apoptosis of neurons. During this period, the expression of B-cell lymphoma/leukemia 2 protein (Bcl-2) increased significantly, whereas the expression of Bcl-2–associated X protein (Bax) and cleaved caspase 3 decreased significantly, indicating the inhibition of apoptosis. Meanwhile, the expression of G protein–coupled receptor 17 decreased, and that of myelin basic protein increased, suggesting that there may be a potential connection between demyelination and neuronal apoptosis. Limitations The limitations of the study include deviations in the preparation of SCI models; lack of reverse validation of molecular mechanisms; absence of in vitro cell experiments; and only one time point after SCI was studied. Conclusions HBO and EPO treatments are beneficial for SCI, especially when the 2 therapies are combined.

Evaluation of the effect of myelotomy on nerve function in rats with spinal cord injury by diffusion tensor imaging

2020 ◽  
pp. 028418512097518
Author(s):  
Yi Liu ◽  
Changbin Liu ◽  
Chuan Qin ◽  
Xin Zhang ◽  
Hao Feng ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Diffusion Tensor Imaging ◽  
Diffusion Tensor ◽  
Pearson Correlation ◽  
Mean Diffusivity ◽  
Motor Dysfunction ◽  
Sprague Dawley ◽  
Cord Injury ◽  
Pearson Correlation Test

Background Spinal cord injury (SCI) is a severe central nervous system injury that can generally induce different degrees of sensory and motor dysfunction Purpose To clarify the changes of diffusion tensor imaging (DTI) parameters after spinal cord myelotomy in rats with SCI. Material and Methods Eighteen Sprague Dawley (SD) rats were randomly divided into the Sham group (n=6), SCI group (n=6), and Mye group (n=6), respectively. The DTI values at 1, 3, 7, and 21 days after modeling were collected by magnetic resonance imaging (MRI). The spinal specimen at the injury site was collected on the 21st day for Nissl’s staining to assess the changes in neurons. Results The fractional anisotropy (FA) values in both the SCI group and Mye group significantly decreased. In addition, the FA values between the two groups were statistically significant ( P < 0.001). The apparent diffusion coefficient (ADC), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values all decreased and then increased ( P < 0.001). Pearson correlation test showed that the ADC, MD, and AD values were positively correlated with the Basso Beattie Bresnahan (BBB) score. Nissl’s staining showed a higher number of Nissl’s bodies, and deep staining of Nissl’s bodies in the Mye group, while the morphology of neurons was relatively good. The number of neurons in the Mye group was significantly higher after myelotomy compared to the SCI group ( P < 0.001). Conclusion The DTI parameters, especially ADC values, could non-invasively and quantifiably evaluate the efficacy of myelotomy for rats with SCI.

scholarly journals Electroacupuncture ameliorates motor dysfunction via inhibiting p66Shc-mediated oxidative stress and endoplasmic reticulum stress in rats with spinal cord injury

2020 ◽  
Author(s):  
Fusheng Zhao ◽  
Geng Wu ◽  
Yang Wu ◽  
Yunlong Bai ◽  
Yongjia Qiu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Cord Injury ◽  
Activating Transcription Factor

Abstract Background: Spinal cord injury (SCI) is a severe neurological disorder for which there is currently no effective treatment. Electroacupuncture (EA) is a means of combining traditional acupuncture with modern electrotherapy, which has been widely used and verified to have neuroprotective effects. The aim of this study was to evaluate the effects of EA treatment on the repair of SCI and to investigate the possible mechanisms. Methods: Rats were randomly divided into sham, sham+EA, SCI and SCI+EA four groups after SCI model was established. Rat motor function was assessed by the Basso, Beattie and Bresnahan locomotor rating scale, inclined plane test and footprint analysis. Histological alterations were examined with hematoxylin-eosin and Nissl staining. Oxidative stress was evaluated by measuring reactive oxygen species (ROS), glutathione (GSH), total antioxidant capacity (T-AOC), 3-nitrotyrosine (3-NT), as well as 4-hydroxynonenal (4-HNE) levels. The expression of p66Shc and endoplasmic reticulum stress (ERS) were detected to explore the involved mechanisms.Results: EA treatment significantly improved motor functional recovery, reduced spinal cord lesion cavity and neuronal chromatolysis after SCI. Meanwhile, EA treatment alleviated oxidative stress, as indicated by suppression of ROS production, increase in GSH and T-AOC levels and reduction of 3-NT and 4-HNE expression. Further, EA stimulation markedly eliminated the aberrant increase of p66Shc due to SCI in rats. More notably, EA treatment also attenuated ERS via down-regulation of glucose-regulated protein 78, activating transcription factor 4, C/EBP homologous protein, X-box binding protein 1 and activating transcription factor 6 expression in rat spinal cord tissues after SCI. Conclusions: These findings suggest that EA is a potential strategy for treatment of SCI, and the mechanism might be, at least in part, associated with mitigation of p66Shc-mediated oxidative stress and ERS in rats.

scholarly journals Electroacupuncture Ameliorates Motor Dysfunction via Inhibiting p66Shc-Associated Oxidative Stress and Endoplasmic Reticulum Stress in Rats with Spinal Cord Injury

2020 ◽  
Author(s):  
Fusheng Zhao ◽  
Geng Wu ◽  
Yang Wu ◽  
Yunlong Bai ◽  
Yongjia Qiu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Rating Scale ◽  
Motor Dysfunction ◽  
Cord Injury ◽  
Activating Transcription Factor

Abstract Background: Spinal cord injury (SCI) is a severe neurological disorder for which there is currently no effective treatment. Electroacupuncture (EA) is a type of traditional acupuncture combined with modern electrotherapy, which has been widely used and verified to have neuroprotective effects. The aim of this study was to evaluate the effects of EA stimulation on the repair of SCI and to investigate the possible mechanisms. Methods: Sprague-Dawley rats were randomly divided into sham, sham+EA, SCI and SCI+EA four groups. Rat motor function was assessed by the Basso, Beattie and Bresnahan locomotor rating scale, inclined plane test and footprint analysis. Histological alterations of spinal cords were examined with hematoxylin-eosin and Nissl staining. Oxidative stress was evaluated by measuring reactive oxygen species (ROS), glutathione (GSH), total antioxidant capacity (T-AOC), 3-nitrotyrosine (3-NT), and 4-hydroxynonenal (4-HNE) levels. The changes in p66Shc expression and endoplasmic reticulum stress (ERS) were detected to explore the involved mechanisms.Results: EA stimulation significantly improved rat motor functional recovery, reduced spinal cord lesion cavity and neuronal chromatolysis after SCI. Concomitantly, EA stimulation alleviated oxidative stress, as indicated by suppression of ROS production, increase in GSH and T-AOC levels and reduction of 3-NT and 4-HNE expression. Further, EA stimulation markedly eliminated the aberrant increase of p66Shc due to SCI in rats. More notably, EA stimulation was also able to attenuate ERS via down-regulation of glucose-regulated protein 78, activating transcription factor 4, C/EBP homologous protein, X-box binding protein 1 and activating transcription factor 6 expression in rat spinal cord tissues after SCI. Conclusions: These findings suggest that EA is a potential strategy for treatment of SCI, and the mechanism might be, at least in part, associated with mitigation of p66Shc-associated oxidative stress and ERS in rats.

Electrical epidural stimulation of the cervical spinal cord: Implications for spinal respiratory neuroplasticity after spinal cord injury

2021 ◽  
Author(s):  
Ian G Malone ◽  
Rachel L Nosacka ◽  
Marissa A Nash ◽  
Kevin J Otto ◽  
Erica A Dale
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neural Plasticity ◽  
Molecular Mechanisms ◽  
Cervical Spinal Cord ◽  
Motor Nucleus ◽  
Epidural Stimulation ◽  
Locomotor Function ◽  
Lumbosacral Spinal Cord ◽  
Cord Injury

Traumatic cervical spinal cord injury (cSCI) can lead to damage of bulbospinal pathways to the respiratory motor nuclei and consequent life-threatening respiratory insufficiency due to respiratory muscle paralysis/paresis. Reports of electrical epidural stimulation (EES) of the lumbosacral spinal cord to enable locomotor function after SCI are encouraging, with some evidence of facilitating neural plasticity. Here, we detail the development and success of EES in recovering locomotor function with consideration of stimulation parameters and safety measures to develop effective EES protocols. EES is just beginning to be applied in other motor, sensory, and autonomic systems; however, there has only been moderate success in preclinical studies aimed at improving breathing function after cSCI. Thus, we explore rationale for applying EES to the cervical spinal cord, targeting the phrenic motor nucleus for the restoration of breathing. We also suggest cellular/molecular mechanisms by which EES may induce respiratory plasticity including a brief examination of sex-related differences in these mechanisms. Finally, we suggest more attention be paid to the effects of specific electrical parameters that have been used in the development of EES protocols and how that can impact the safety and efficacy for those receiving this therapy. Ultimately, we aim to inform readers about the potential benefits of EES in the phrenic motor system and encourage future studies in this area.

Global Gene Expression Analysis of Rodent Motor Neurons Following Spinal Cord Injury Associates Molecular Mechanisms With Development of Postinjury Spasticity

2010 ◽  
Vol 103 (2) ◽  
pp. 761-778 ◽  
Author(s):  
J. Wienecke ◽  
A-C. Westerdahl ◽  
H. Hultborn ◽  
O. Kiehn ◽  
J. Ryge
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Global Gene Expression ◽  
Motor Dysfunction ◽  
Plateau Potentials ◽  
Endogenous Expression ◽  
Cord Injury

Spinal cord injury leads to severe problems involving impaired motor, sensory, and autonomic functions. After spinal injury there is an initial phase of hyporeflexia followed by hyperreflexia, often referred to as spasticity. Previous studies have suggested a relationship between the reappearance of endogenous plateau potentials in motor neurons and the development of spasticity after spinalization. To unravel the molecular mechanisms underlying the increased excitability of motor neurons and the return of plateau potentials below a spinal cord injury we investigated changes in gene expression in this cell population. We adopted a rat tail-spasticity model with a caudal spinal transection that causes a progressive development of spasticity from its onset after 2 to 3 wk until 2 mo postinjury. Gene expression changes of fluorescently identified tail motor neurons were studied 21 and 60 days postinjury. The motor neurons undergo substantial transcriptional regulation in response to injury. The patterns of differential expression show similarities at both time points, although there are 20% more differentially expressed genes 60 days compared with 21 days postinjury. The study identifies targets of regulation relating to both ion channels and receptors implicated in the endogenous expression of plateaux. The regulation of excitatory and inhibitory signal transduction indicates a shift in the balance toward increased excitability, where the glutamatergic N-methyl-d-aspartate receptor complex together with cholinergic system is up-regulated and the γ-aminobutyric acid type A receptor system is down-regulated. The genes of the pore-forming proteins Cav1.3 and Nav1.6 were not up-regulated, whereas genes of proteins such as nonpore-forming subunits and intracellular pathways known to modulate receptor and channel trafficking, kinetics, and conductivity showed marked regulation. On the basis of the identified changes in global gene expression in motor neurons, the present investigation opens up for new potential targets for treatment of motor dysfunction following spinal cord injury.

The role of multiple hyperbaric oxygenation in expanding therapeutic windows after acute spinal cord injury in rats

2003 ◽  
Vol 99 (2) ◽  
pp. 198-205 ◽  
Author(s):  
Lixin Huang ◽  
Maheshkumar P. Mehta ◽  
Anil Nanda ◽  
John H. Zhang
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Hyperbaric Oxygenation ◽  
Rating Scale ◽  
Therapeutic Window ◽  
Content Type ◽  
Cord Injury ◽  
Weight Drop ◽  
Fine Print

Object. Hyperbaric oxygenation (HBO) therapy has been reported to improve neurological recovery after spinal cord injury (SCI). In the present study, the authors examined whether multiple HBO therapy can expand the therapeutic window after acute SCI. Methods. Seventy rats were randomly assigned to seven groups: sham surgery; SCI without treatment; single HBO treatment beginning at 30 minutes, 3 hours, and 6 hours after SCI; and multiple HBO treatments starting at 6 and 24 hours postinjury. Mild SCI was induced by adjusting the height of a weight drop (10 g) to 6.25 mm above the exposed spinal cord. A single HBO administration was performed at 2.82 ata for 1 hour. The multiple HBO treatment modality was performed once daily for 1 week. All rats underwent behavioral testing with the Basso-Beattie-Breshnahan locomotor rating scale twice a week. Rats were killed on Day 42 postinjury and specimens comprising the lesioned area were histopathologically examined. Those rats that received single HBO intervention beginning at 30 minutes and 3 hours and those that received multiple HBO treatment starting at 6 hours following injury made significantly greater neurological recoveries than those in the nontreatment SCI group. These rats also retained more sparing tissue than controls. Conclusions. The results of this study demonstrate that multiple HBO treatments can expand the therapeutic window for acute SCI to 6 hours after injury.

scholarly journals Up-regulation of MicroRNAs-21 and -223 in a Sprague-Dawley Rat Model of Traumatic Spinal Cord Injury

2020 ◽  
Vol 10 (3) ◽  
pp. 141
Author(s):  
Hyo-Jin Chung ◽  
Wook-Hun Chung ◽  
Sun-Hee Do ◽  
Jae-Hoon Lee ◽  
Hwi-yool Kim
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Rat Model ◽  
Rating Scale ◽  
Quantitative Polymerase Chain Reaction ◽  
Balloon Catheter ◽  
Traumatic Spinal Cord Injury ◽  
Sprague Dawley ◽  
Time Points ◽  
Cord Injury

In this experimental animal study, we examined alterations in the degree of transcription of two microRNAs (miRs)—miR-21 and -223—in a Sprague-Dawley (SD) rat model of traumatic spinal cord injury (TSCI). Depending on the volume of the balloon catheter (V), a total of 75 male SD rats were divided into the three experimental groups: the sham group (n = 25; V = 0 μL), the mild group (n = 25; V = 20 μL), and the severe group (n = 25; V = 50 μL). Successful induction of TSCI was confirmed on both locomotor rating scale at 4 h and 1, 3 and 7 days post-lesion and histopathologic examinations. Then, RNA isolation and quantitative polymerase chain reaction (PCR) were performed. No differences in the level of miR-21 expression were found at the first time point studied (4 h post-lesion) between the three experimental groups, whereas such differences were significant at all the other time points (p < 0.05). Moreover, there were significant alterations in the level of miR-223 expression at all time points studied through all the experimental groups (p < 0.05). Furthermore, locomotor rating scale scores had a linear relationship with the level of miR-21 expression (R2 = 0.4363, Y = 1.661X + 3.096) and that of miR-223 one (R2 = 0.9104, Y = 0.8385X + 2.328). Taken together, we conclude that up-regulation of miR-21 and -223 might be closely associated with progression and the early course of TSCI, respectively.

A simple and reliable behavioral analysis of locomotor function after spinal cord injury in mice

2002 ◽  
Vol 97 (1) ◽  
pp. 142-147 ◽  
Author(s):  
Yuji Mikami ◽  
Masahiro Toda ◽  
Masahiko Watanabe ◽  
Masaya Nakamura ◽  
Yoshiaki Toyama ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Rating Scale ◽  
Animal Movement ◽  
Vertical Movement ◽  
Behavioral Analysis ◽  
Content Type ◽  
Locomotor Function ◽  
Cord Injury ◽  
Fine Print

✓ To establish a simple and reliable method to assess the behavioral function after spinal cord injury (SCI) in mice, the authors used an automated animal movement analysis system, SCANET. Two different SCI lesions were created in adult female BALB/c and C57BL/6 mice by transecting both the posterior columns and the left lateral and anterior funiculi or only the left lateral and anterior funiculi at T-8. Control mice underwent laminectomy only. The SCANET system consists of a cage equipped with two crossing sensor frames arranged at different heights, by which small (M1) and large (M2) horizontal movements and the vertical movement involved in rearing (RG) can be monitored. The authors assessed locomotor function by determining the M1, M2, and RG scores; to this end, they used the SCANET system and a previously established behavior test, the 21-point open-field Basso-Beattie-Bresnahan (BBB) Locomotor Rating Scale. The results indicated that the RG scores were significantly and consistently different between the spinal cord—injured and control mice, irrespective of the mouse strain or injury model, but that M1 and M2 scores were not. Moreover, there was a statistically positive correlation between the RG score and the BBB Scale score. For the assessment of locomotor function after SCI, use of the SCANET sytem in behavioral analysis is simple and the method is highly reproducible. The analysis of vertical movement is useful for assessing the recovery of limb function in mice following thoracic hemisection.

scholarly journals Knockdown of long non-coding RNA LEF1-AS1 attenuates apoptosis and inflammatory injury of microglia cells following spinal cord injury

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Sheng-Yu Cui ◽  
Wei Zhang ◽  
Zhi-Ming Cui ◽  
Hong Yi ◽  
Da-Wei Xu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cell Viability ◽  
Microglial Cells ◽  
Protective Effects ◽  
Loss Of Function ◽  
Sprague Dawley ◽  
Cord Injury ◽  
Apoptosis And Inflammation

Abstract Background Spinal cord injury (SCI) is associated with health burden both at personal and societal levels. Recent assessments on the role of lncRNAs in SCI regulation have matured. Therefore, to comprehensively explore the function of lncRNA LEF1-AS1 in SCI, there is an urgent need to understand its occurrence and development. Methods Using in vitro experiments, we used lipopolysaccharide (LPS) to treat and establish the SCI model primarily on microglial cells. Gain- and loss of function assays of LEF1-AS1 and miR-222-5p were conducted. Cell viability and apoptosis of microglial cells were assessed via CCK8 assay and flow cytometry, respectively. Adult Sprague-Dawley (SD) rats were randomly divided into four groups: Control, SCI, sh-NC, and sh-LEF-AS1 groups. ELISA test was used to determine the expression of TNF-α and IL-6, whereas the protein level of apoptotic-related markers (Bcl-2, Bax, and cleaved caspase-3) was assessed using Western blot technique. Results We revealed that LncRNA LEF1-AS1 was distinctly upregulated, whereas miR-222-5p was significantly downregulated in LPS-treated SCI and microglial cells. However, LEF1-AS1 knockdown enhanced cell viability, inhibited apoptosis, as well as inflammation of LPS-mediated microglial cells. On the contrary, miR-222-5p upregulation decreased cell viability, promoted apoptosis, and inflammation of microglial cells. Mechanistically, LEF1-AS1 served as a competitive endogenous RNA (ceRNA) by sponging miR-222-5p, targeting RAMP3. RAMP3 overexpression attenuated LEF1-AS1-mediated protective effects on LPS-mediated microglial cells from apoptosis and inflammation. Conclusion In summary, these findings ascertain that knockdown of LEF1-AS1 impedes SCI progression via the miR-222-5p/RAMP3 axis.

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